TITLE: Endocannabinoid System and Brain Network Function in Late-Life Depression PROJECT SUMMARY/ABSTRACT During the past two decades, multiple pathophysiological mechanisms have been hypothesized to alter brain circuitry and explain the clinical heterogeneity of late-life major depression (LLD). Despite the diverse etiology of LLD, primary treatments have focused on modifying monoamine systems with limited effectiveness. Novel therapeutic targets are therefore clearly needed. Mounting evidence implicates the endocannabinoid signaling (ECS) system in the pathophysiology of major depression. However, its role in the neurobiologic underpinnings of depression in the elderly is currently unknown; this critical gap in knowledge is addressed in this study. This proposal's overall objective is to determine components of the ECS system and functional brain network features associated with LLD occurrence, and with two common symptom dimensions of LLD (low mood and anhedonia). Task-dependent functional MRI (T-fMRI) and resting-state functional connectivity MRI [R-fcMRI]) will be used to probe the emotional reactivity and ventral striatal brain network functioning, and peripheral endocannabinoid measures will be obtained to determine the functioning of the ECS system. Our central hypothesis is that reduced ECS in older adults with depression is associated with hyperactive amygdala and hypoactive ventral striatal functional activity, and disrupted functional connectivity in these brain networks. To achieve our objective, a total of 80 older adults (>60 years of age) will enrolled into the following groups that are equated for age and gender: (1) LLD (n = 50) and (2) healthy comparison (HC) (n = 30) subjects. This study employs a cross-sectional study design wherein the following aims will be completed: Aim 1. To determine the relationships between measures of brain network function and markers of the ECS system in subjects with LLD. Extensive clinical assessments will be conducted in antidepressant-free patients with LLD and in HC participants. These biologic measures will also be obtained: Brain network function (using task functional MRI paradigms and resting-state functional connectivity MRI) and peripheral ECS measures. Aim 2. To determine the relationships between brain network function and ECS measures and symptom dimensions in subjects with LLD. LLD and HC participants will also complete behavioral and self-report clinical measures of depressed mood and hedonic capacity. The stage will be set for future seminal research that uses ECS and brain network function measures as biomarkers to aid diagnosis by parsing LLD patients into more homogeneous subtypes, to predict and monitor outcomes to specific treatment interventions, and to guide selection of optimal treatment for individual patients prior to initiation.